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Discovery and in Vitro Optimization of 3-Sulfamoylbenzamides as ROMK Inhibitors.

Abstract：

:Inhibitors of the renal outer medullary potassium channel (ROMK) show promise as novel mechanism diuretics, with potentially lower risk of diuretic-induced hypokalemia relative to current thiazide and loop diuretics. Here, we report the identification of a novel series of 3-sulfamoylbenzamide ROMK inhibitors. Starting from HTS hit 4, this series was optimized to provide ROMK inhibitors with good in vitro potencies and well-balanced ADME profiles. In contrast to previously reported small-molecule ROMK inhibitors, members of this series were demonstrated to be highly selective for inhibition of human over rat ROMK and to be insensitive to the N171D pore mutation that abolishes inhibitory activity of previously reported ROMK inhibitors.

journal_name

ACS Med Chem Lett

journal_title

ACS medicinal chemistry letters

authors

Sammons MF,Kharade SV,Filipski KJ,Boehm M,Smith AC,Shavnya A,Fernando DP,Dowling MS,Carpino PA,Castle NA,Zellmer SG,Antonio BM,Gosset JR,Carlo A,Denton JS

doi

10.1021/acsmedchemlett.7b00481

subject

Has Abstract

pub_date

2018-01-19 00:00:00

pages

125-130

issue

2

issn

1948-5875

journal_volume

9

pub_type

杂志文章

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